Marcinkowska Monika, Stanczyk Maciej, Janaszewska Anna, Gajek Arkadiusz, Ksiezak Malgorzata, Dzialak Paula, Klajnert-Maculewicz Barbara
Department of General Biophysics, Faculty of Biology and Environmental Protection, University of Lodz, Pomorska 141/143, 90-236 Lodz, Poland.
Department of Surgical Oncology, Cancer Center, Copernicus Memorial Hospital, 93-513 Lodz, Poland.
Polymers (Basel). 2019 Aug 29;11(9):1422. doi: 10.3390/polym11091422.
Taxanes are considered fundamental drugs in the treatment of breast cancer, but despite the similarities, docetaxel (doc) and paclitaxel (ptx) work differently. For this reason, it is interesting to identify mechanisms of antitumor activity of PAMAM dendrimer conjugates that carry docetaxel or paclitaxel and monoclonal antibody trastuzumab, specifically targeted to cells which overexpressed HER-2. For this purpose, the impact on the level of reactive oxygen species, the mitochondrial membrane potential, cell cycle distribution and the activity of caspases-3/7, -8 and -9 of PAMAM-doc-trastuzumab and PAMAM-ptx-trastuzumab conjugates was determined and compared with free docetaxel and paclitaxel toward HER-2-positive (SKBR-3) and negative (MCF-7) human breast cancer cell lines. Moreover, apoptosis and necrosis were studied using flow cytometry and confocal microscopy, respectively. Our studies show the complexity of the potential mechanism of cytotoxic action of PAMAM-drug-trastuzumab conjugates that should be sought as a resultant of oxidative stress, mitochondrial activation of the caspase cascade and the HER-2 receptor blockade.
紫杉烷类被认为是乳腺癌治疗中的基础药物，但尽管多西他赛（doc）和紫杉醇（ptx）有相似之处，它们的作用方式却有所不同。因此，确定携带多西他赛或紫杉醇以及单克隆抗体曲妥珠单抗的聚酰胺-胺（PAMAM）树枝状大分子缀合物的抗肿瘤活性机制很有意思，该缀合物特异性靶向过表达HER-2的细胞。为此，测定了PAMAM-doc-曲妥珠单抗和PAMAM-ptx-曲妥珠单抗缀合物对活性氧水平、线粒体膜电位、细胞周期分布以及半胱天冬酶-3/7、-8和-9活性的影响，并将其与游离多西他赛和紫杉醇对HER-2阳性（SKBR-3）和阴性（MCF-7）人乳腺癌细胞系的影响进行比较。此外，分别使用流式细胞术和共聚焦显微镜研究了细胞凋亡和坏死情况。我们的研究表明，PAMAM-药物-曲妥珠单抗缀合物潜在的细胞毒性作用机制很复杂，应将其视为氧化应激、半胱天冬酶级联反应的线粒体激活以及HER-2受体阻断的综合结果来探寻。
